Segment

4
Wake & REM: Monoamines

Neurobiology of Sleep
and Wakefulness
Learning Points & Defining Behavioral States
Historical Overview: Brainstem & Forebrain
Wakefulness and REM Sleep: Monoamines,
Acetylcholine & GABA, Hypocretin/Orexin
NREM Sleep: GABA, Adenosine
Summary

Monoaminergic Components of the

Ascending Reticular Activating System

Serotonin, Norepinephrine, and Histamine

Neurons Cease Discharging in REM Sleep
Neuron
EEG
Eyes
Muscle
WAKE

NREM

REM

Jacobs and Fornal, in Handbook of Behavioral State Control, CRC Press 1999, p. 184

 Serotonergic, noradrenergic, and

histaminergic neurons all have a
Wake-On/REM-Off discharge pattern
However, each of these neurochemical
cell types has waking discharge
patterns that differ from the other cell
types

Serotonergic DR Neurons Discharge

Regularly During Wakefulness

Lydic et al., Am J Physiol 247:R135-R145, 1984

NE-LC Neurons Discharge Irregularly

During Wakefulness
EMG

500 V

EEG

500 V

Unit

1 mV

Takahashi et al., 2010

Neuroscience 169: 1115-26

HA-TMN Neurons Slow Firing Rate

from Active to Quiet Wakefulness
AcBve Waking
EMG
EEG
Unit
EMG
EEG
Unit

Quiet Waking

Takahashi et al., J Neurosci 26:10292-10298, 2006

 Serotonergic, noradrenergic, and

histaminergic neurons also discharge
with dierent phase relaBonships to
changes in behavioral state

NE-LC Neurons Resume Discharging

Before the Onset of Wakefulness

Takahashi et al., Neuroscience 169:1115-1126, 2010

HA-TMN Neurons Resume Discharging

After the Onset of Wakefulness

Takahashi et al., J Neurosci 26:10292-10298, 2006

Histamine Promotes Wakefulness

Knockout mice lacking the histidine
decarboxylase gene show an increase in
REM sleep, a slowing of EEG frequencies
during wakefulness, and a short sleep
latency when placed in a new environment
HDC +/+

HDC -/-

Parmentier et al., J Neurosci 22:7695-7711, 2002

Histamine Promotes Wakefulness

Knockout mice lacking the histidine
decarboxylase gene show an increase in
REM sleep, a slowing of EEG frequencies
during wakefulness, and a short sleep
latency when placed in a new environment
This finding supports a role for histamine in
maintaining wakefulness
Parmentier et al., J Neurosci 22:7695-7711, 2002

State-Specific Changes in
Brain Levels of Monoamines
In every brain region studied, levels of serotonin,
norepinephrine, and histamine are greater during
wakefulness than during sleep

Wakefulness

NREM Sleep

REM Sleep

NE LC Neurons Maintain the

Normal Duration of Wakefulness
Use of optogenetic tools to inhibit LC neurons:
decreased the duration of wakefulness episodes
increased the number of wake-to-NREM transitions
increased cortical slow wave activity during wakefulness

Use of optogenetic tools to stimulate LC neurons:

caused immediate transitions to wakefulness from NREM
and REM sleep
Carter et al., Nat Neurosci 13: 1526-1533, 2010

Monoamines Promote
Wakefulness: Clinical Relevance
Selective serotonin (SSRIs) and serotoninnorepinephrine (SNRIs) enhance the actions of these
two wake-promoting neurotransmitters
SSRIs and SNRIs are widely used for the treatment of
depression
Insomnia or disturbed sleep are common side effects
of SSRIs and SNRIs

Monoamines Promote
Wakefulness: Clinical Relevance
Patients with major depressive disorder often
have coexisting insomnia that does not
improve with antidepressant treatment
Combining the use of an SSRI (fluoxetine) with
a sleeping medication (eszopiclone) increases
the antidepressant response and improves
sleep (Fava et al., Biol Psychiatry 59:1052-1060, 2006)

Monoamines Promote
Wakefulness: Clinical Relevance
Doxepin improves sleep in adults

(Roth et al., Sleep

and
with primary

30:1555-1561, 2007; Krystal et al., Sleep 34:1433-1442, 2011)

elderly (Krystal et al., Sleep 33:1553-1561, 2010)

insomnia

Modafinil increases the activity of wakefulnesspromoting histaminergic neurons in the TMN

(Scammell et al., J Neurosci 15:8620-8628, 2000)